tbuckley/cabot-search huggingface dataset:
Right ventricular dysfunction in patients with new‐onset heart failure: longitudinal follow‐up during guideline‐directed medical therapy
Authors: Mohammad Mostafa Ansari Ramandi, Joost P. van Melle, Thomas M. Gorter, Elke S. Hoendermis, Dirk J. van Veldhuisen, Jan F. Nauta, Martje H.L. van der Wal, Janke Warink‐Riemersma, Adriaan A. Voors, Michael G. Dickinson
Journal: European Journal of Heart Failure (2022)

Improvement in left ventricular ejection fraction (LVEF) after up-titration of guideline-directed medical therapy (GDMT) has been well described in heart failure (HF) patients. Less is known about the prevalence and clinical course of right ventricular dysfunction (RVD) in patients with new-onset HF.From 2012 to 2018, 625 patients with a recent (<3 months) diagnosis of HF were referred to a specialized nurse-led HF clinic for protocolized up-titration of GDMT. RVD, defined as tricuspid annular plane systolic excursion (TAPSE) <17 mm, was assessed at baseline and at the follow-up visit. Patients were followed for the combined endpoint of all-cause mortality and HF hospitalization for a mean of 3.3 ± 1.9 years. Of the 625 patients, 241 (38.6%) patients had RVD at baseline. Patients with RVD were older, more symptomatic, had a lower LVEF, and more often had a history of cardiothoracic surgery and atrial fibrillation. After a median follow-up of 9 months, right ventricular function normalized in 49% of the patients with baseline RVD. RVD at baseline was associated with a higher risk of the combined endpoint (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.21-2.18). Right ventricular function normalization was associated with a lower risk for the combined endpoint (HR 0.56, 95% CI 0.31-0.99), independent of baseline TAPSE, age, sex, and LVEF.More than one-third of patients with new-onset HF have RVD. RVD is associated with a higher risk of all-cause mortality and HF hospitalization. Recovery of RVD regularly occurs during up-titration of GDMT and is associated with improved clinical outcomes.
Evolutionary dynamics of pseudoautosomal region 1 in humans and great apes
Authors: Juraj Bergman, Mikkel Heide Schierup
Journal: Genome biology (2022)

Abstract Background The pseudoautosomal region 1 (PAR1) is a 2.7 Mb telomeric region of human sex chromosomes. PAR1 has a crucial role in ensuring proper segregation of sex chromosomes during male meiosis, exposing it to extreme recombination and mutation processes. We investigate PAR1 evolution using population genomic datasets of extant humans, eight populations of great apes, and two archaic human genome sequences. Results We find that PAR1 is fast evolving and closer to evolutionary nucleotide equilibrium than autosomal telomeres. We detect a difference between substitution patterns and extant diversity in PAR1, mainly driven by the conflict between strong mutation and recombination-associated fixation bias at CpG sites. We detect excess C-to-G mutations in PAR1 of all great apes, specific to the mutagenic effect of male recombination. Despite recent evidence for Y chromosome introgression from humans into Neanderthals, we find that the Neanderthal PAR1 retained similarity to the Denisovan sequence. We find differences between substitution spectra of these archaics suggesting rapid evolution of PAR1 in recent hominin history. Frequency analysis of alleles segregating in females and males provided no evidence for recent sexual antagonism in this region. We study repeat content and double-strand break hotspot regions in PAR1 and find that they may play roles in ensuring the obligate X-Y recombination event during male meiosis. Conclusions Our study provides an unprecedented quantification of population genetic forces governing PAR1 biology across extant and extinct hominids. PAR1 evolutionary dynamics are predominantly governed by recombination processes with a strong impact on mutation patterns across all species.
Emerging Evidence on Coronary Heart Disease Screening in Kidney and Liver Transplantation Candidates: A Scientific Statement From the American Heart Association
Authors: Xingxing S. Cheng, Lisa B. VanWagner, Salvatore P. Costa, David A. Axelrod, Sripal Bangalore, Silas P. Norman, Charles A. Herzog, Krista L. Lentine
Journal: Circulation (2022)

Coronary heart disease is an important source of mortality and morbidity among kidney transplantation and liver transplantation candidates and recipients and is driven by traditional and nontraditional risk factors related to end-stage organ disease. In this scientific statement, we review evidence from the past decade related to coronary heart disease screening and management for kidney and liver transplantation candidates. Coronary heart disease screening in asymptomatic kidney and liver transplantation candidates has not been demonstrated to improve outcomes but is common in practice. Risk stratification algorithms based on the presence or absence of clinical risk factors and physical performance have been proposed, but a high proportion of candidates still meet criteria for screening tests. We suggest new approaches to pretransplantation evaluation grounded on the presence or absence of known coronary heart disease and cardiac symptoms and emphasize multidisciplinary engagement, including involvement of a dedicated cardiologist. Noninvasive functional screening methods such as stress echocardiography and myocardial perfusion scintigraphy have limited accuracy, and newer noninvasive modalities, especially cardiac computed tomography-based tests, are promising alternatives. Emerging evidence such as results of the 2020 International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease trial emphasizes the vital importance of guideline-directed medical therapy in managing diagnosed coronary heart disease and further questions the value of revascularization among asymptomatic kidney transplantation candidates. Optimizing strategies to disseminate and implement best practices for medical management in the broader end-stage organ disease population should be prioritized to improve cardiovascular outcomes in these populations.
Swelling‐Mediated Mechanical Stimulation Regulates Differentiation of Adipose‐Derived Mesenchymal Stem Cells for Intervertebral Disc Repair Using Injectable UCST Microgels
Authors: Xianpeng Huang, Di Chen, Chengzhen Liang, Kesi Shi, Xiaopeng Zhou, Yuang Zhang, Yi Li, Jiangjie Chen, Kaishun Xia, Jiawei Shu, Biao Yang, Jingkai Wang, Haibin Xu, Chao Yu, Feng Cheng, Shaoke Wang, Yongxiang Zhang, Chenggui Wang, Liwei Ying, Hao Li, Meiling Han, Fangcai Li, Yiqing Tao, Qian Zhao, Qixin Chen
Journal: Advanced Healthcare Materials (2022)

Mechanical stimulation is an effective approach for controlling stem cell differentiation in tissue engineering. However, its realization in in vivo tissue repair remains challenging since this type of stimulation can hardly be applied to injectable seeding systems. Here, it is presented that swelling of injectable microgels can be transformed to in situ mechanical stimulation via stretching the cells adhered on their surface. Poly(acrylamide-co-acrylic acid) microgels with the upper critical solution temperature property are fabricated using inverse emulsion polymerization and further coated with polydopamine to increase cell adhesion. Adipose-derived mesenchymal stem cells (ADSCs) adhered on the microgels can be omnidirectionally stretched along with the responsive swelling of the microgels, which upregulate TRPV4 and Piezo1 channel proteins and enhance nucleus pulposus (NP)-like differentiation of ADSCs. In vivo experiments reveal that the disc height and extracellular matrix content of NP are promoted after the implantation with the microgels. The findings indicate that swelling-induced mechanical stimulation has great potential for regulating stem cell differentiation during intervertebral disc repair.
The NCATS Assay Guidance Manual programme: advancing the practice and rigour of preclinical translation
Authors: Sarine Markossian, Kyle R. Brimacombe, G. Sitta Sittampalam, Abigail Grossman, Nathan P. Coussens, James Inglese, Douglas S. Auld, William Chin, Christopher P. Austin, Matthew D. Hall
Journal: Nature Reviews Drug Discovery (2022)
Optimize treatment approaches in isocitrate dehydrogenase (IDH) mutant gliomas: open issues
Authors: Roberta Rudà
Journal: Neuro-Oncology (2022)

The 2021 update of the World Health Organization (WHO) Classification of Central Nervous System Tumors1 has reinforced the integration of molecular data with conventional histological features for both diagnosis and treatment of diffuse gliomas. Mutations in isocitrate dehydrogenase (IDH) genes, IDH1 and IDH2, that represent an early event in gliomagenesis, are strong determinant of an improved overall survival in association with 1p/19q codeletion. Thus, the WHO 2021 Classification recognizes WHO grade 2 and 3 IDH-mutant astrocytomas and IDH-mutant, 1p/19q codeleted oligodendrogliomas. Moreover, as CDKN2A/B homozygous deletion has been associated with shorter survival, its presence in an IDH-mutant astrocytoma will qualify the tumor as a WHO grade 4 regardless of a lower grade histological appearance. In this issue of Neuro-Oncology Miller, Gonzalez Castro, and co-authors2 have exhaustively and critically reviewed the state of art and future directions of diagnosis and management of IDH-mutant gliomas. Overall, the WHO Classification 2021 has raised the issue of how to optimize and personalize standard and novel treatments in IDH-mutant gliomas. Supramaximal resection has been suggested to improve progression-free and overall survival in lower grade diffuse gliomas3; however, there is need to examine larger cohort of patients to see whether this is true for either IDH-mutant astrocytomas or IDH-mutant, 1p/19q codeleted oligodendrogliomas or both. The same question applies to reoperation, which is increasingly pursued: based on the more indolent natural course, one could hypothesize a higher relevance in IDH-mutant, 1p/19q codeleted oligodendrogliomas versus IDH-mutant astrocytomas in order to delay the need for radiotherapy and the risk of cognitive deficit in very long surviving patients. The role of adjuvant radiotherapy and chemotherapy for the new category of IDH-mutant astrocytomas with CDKN2A/B homozygous deletion, that represents a poorer prognostic group, needs to be defined: radiotherapy and adjuvant temozolomide, as demonstrated in the CATNON trial on anaplastic gliomas without 1p/19q codeletion, or radiotherapy with concomitant and adjuvant temozolomide, as in grade 4 IDH-wild type glioblastomas?
A Bioinspired Orthopedic Biomaterial with Tunable Mechanical Properties Based on Sintered Titanium Fibers
Authors: Matthias Rüger, Andreas Martin Seitz, Katja Nuss, Brigitte von Rechenberg, Daniel Seitz, Cris Kostmann, Peter Quadbeck, Olaf Andersen, Caitlyn Collins
Journal: Advanced Healthcare Materials (2022)

Inadequate mechanical compliance of orthopedic implants can result in excessive strain of the bone interface, and ultimately, aseptic loosening. It is hypothesized that a fiber-based biometal with adjustable anisotropic mechanical properties can reduce interface strain, facilitate continuous remodeling, and improve implant survival under complex loads. The biometal is based on strategically layered sintered titanium fibers. Six different topologies are manufactured. Specimens are tested under compression in three orthogonal axes under 3-point bending and torsion until failure. Biocompatibility testing involves murine osteoblasts. Osseointegration is investigated by micro-computed tomography and histomorphometry after implantation in a metaphyseal trepanation model in sheep. The material demonstrates compressive yield strengths of up to 50 MPa and anisotropy correlating closely with fiber layout. Samples with 75% porosity are both stronger and stiffer than those with 85% porosity. The highest bending modulus is found in samples with parallel fiber orientation, while the highest shear modulus is found in cross-ply layouts. Cell metabolism and morphology indicate uncompromised biocompatibility. Implants demonstrate robust circumferential osseointegration in vivo after 8 weeks. The biometal introduced in this study demonstrates anisotropic mechanical properties similar to bone, and excellent osteoconductivity and feasibility as an orthopedic implant material.
iDNA-ABF: multi-scale deep biological language learning model for the interpretable prediction of DNA methylations
Authors: Junru Jin, Yingying Yu, Ruheng Wang, Xin Zeng, Chao Pang, Yi Jiang, Zhongshen Li, Yutong Dai, Ran Su, Quan Zou, Kenta Nakai, Leyi Wei
Journal: Genome biology (2022)

Abstract In this study, we propose iDNA-ABF, a multi-scale deep biological language learning model that enables the interpretable prediction of DNA methylations based on genomic sequences only. Benchmarking comparisons show that our iDNA-ABF outperforms state-of-the-art methods for different methylation predictions. Importantly, we show the power of deep language learning in capturing both sequential and functional semantics information from background genomes. Moreover, by integrating the interpretable analysis mechanism, we well explain what the model learns, helping us build the mapping from the discovery of important sequential determinants to the in-depth analysis of their biological functions.
Paul Wilkinson: environmental epidemiologist at the forefront of research into the health benefits of climate change action
Authors: Penny Warren
Journal: BMJ (2022)

We used the chromatic visual evoked potential, the cVEP, to study responses in human visual cortex evoked by equiluminant color stimuli for six male and 11 female observers. Large-area, colored squares were used to stimulate Single-Opponent cells preferentially, and fine color-checkerboard stimuli were used to activate Double-Opponent responses preferentially. Stimuli were modulated along two directions in color space: 1) the cardinal direction, L-M or M-L of DKL space; 2) the line from the white point to the color of the Red LED in the display screen, which was roughly intermediate between the L-M and -S directions in DKL space in cone-contrast coordinates. The amplitudes of cVEPs to large squares were smaller than those to checkerboards, and latency of the cVEP response to squares was significantly less than the checkerboard latency. The latency of cVEP responses to the squares varied little with cone-contrast unlike the steep reduction of latency with cone-contrast observed in responses to color checkerboard patterns. The dynamic differences between cVEPs to squares and checkerboards support the hypothesis that a distinct neuronal mechanism responded to squares: Single-Opponent cells. Response amplitude, latency, and transientness –and their dependences on cone contrast– were similar in the responses in the L-M and Red color directions. The similarity supports the hypothesis that the Single-Opponent signals in the cVEP come from a distinct population of cells that receive subtractive inputs from L and M cones, either L-M or M-L. <b>Significance Statement:</b> This paper is about characterizing the visual behavior of a distinct population of neurons in the human visual cortex, the Single-Opponent color cells. Based on single-cell results in the visual cortex of Macaque monkeys, we used large uniformly-colored stimuli to isolate the responses of Single-Opponent cells in the chromatic visual evoked potential (cVEP) recorded on the scalp of human observers. VEP signals recorded under conditions believed to reveal Single-Opponent responses are small and transient. Their time course is relatively unaffected by cone-contrast, and they are relatively insensitive to stimulus modulation of short-wavelength-sensitive S cones. Because Single-Opponent cells convey signals that can be used to judge the color of scene illumination, knowing their visual properties is important for understanding color vision.
Tau interactome and RNA binding proteins in neurodegenerative diseases
Authors: Tomas Kavanagh, Aditi Halder, Eleanor Drummond
Journal: Molecular Neurodegeneration (2022)

Pathological tau aggregation is a primary neuropathological feature of many neurodegenerative diseases. Intriguingly, despite the common presence of tau aggregates in these diseases the affected brain regions, clinical symptoms, and morphology, conformation, and isoform ratio present in tau aggregates varies widely. The tau-mediated disease mechanisms that drive neurodegenerative disease are still unknown. Tau interactome studies are critically important for understanding tauopathy. They reveal the interacting partners that define disease pathways, and the tau interactions present in neuropathological aggregates provide potential insight into the cellular environment and protein interactions present during pathological tau aggregation. Here we provide a combined analysis of 12 tau interactome studies of human brain tissue, human cell culture models and rodent models of disease. Together, these studies identified 2084 proteins that interact with tau in human tissue and 1152 proteins that interact with tau in rodent models of disease. Our combined analysis of the tau interactome revealed consistent enrichment of interactions between tau and proteins involved in RNA binding, ribosome, and proteasome function. Comparison of human and rodent tau interactome studies revealed substantial differences between the two species. We also performed a second analysis to identify the tau interacting proteins that are enriched in neurons containing granulovacuolar degeneration or neurofibrillary tangle pathology. These results revealed a timed dysregulation of tau interactions as pathology develops. RNA binding proteins, particularly HNRNPs, emerged as early disease-associated tau interactors and therefore may have an important role in driving tau pathology.
Evaluation of cell-cell interaction methods by integrating single-cell RNA sequencing data with spatial information
Authors: Zhaoyang Liu, Dongqing Sun, Chenfei Wang
Journal: Genome biology (2022)

Abstract Background Cell-cell interactions are important for information exchange between different cells, which are the fundamental basis of many biological processes. Recent advances in single-cell RNA sequencing (scRNA-seq) enable the characterization of cell-cell interactions using computational methods. However, it is hard to evaluate these methods since no ground truth is provided. Spatial transcriptomics (ST) data profiles the relative position of different cells. We propose that the spatial distance suggests the interaction tendency of different cell types, thus could be used for evaluating cell-cell interaction tools. Results We benchmark 16 cell-cell interaction methods by integrating scRNA-seq with ST data. We characterize cell-cell interactions into short-range and long-range interactions using spatial distance distributions between ligands and receptors. Based on this classification, we define the distance enrichment score and apply an evaluation workflow to 16 cell-cell interaction tools using 15 simulated and 5 real scRNA-seq and ST datasets. We also compare the consistency of the results from single tools with the commonly identified interactions. Our results suggest that the interactions predicted by different tools are highly dynamic, and the statistical-based methods show overall better performance than network-based methods and ST-based methods. Conclusions Our study presents a comprehensive evaluation of cell-cell interaction tools for scRNA-seq. CellChat, CellPhoneDB, NicheNet, and ICELLNET show overall better performance than other tools in terms of consistency with spatial tendency and software scalability. We recommend using results from at least two methods to ensure the accuracy of identified interactions. We have packaged the benchmark workflow with detailed documentation at GitHub ( https://github.com/wanglabtongji/CCI ).
Local CpG density affects the trajectory and variance of age-associated DNA methylation changes
Authors: Jonathan Higham, Lyndsay Kerr, Qian Zhang, Rosie M. Walker, Sarah E. Harris, David M. Howard, Emma L. Hawkins, Anca-Larisa Sandu, J. Douglas Steele, Gordon D. Waiter, Alison D. Murray, Kathryn L. Evans, Andrew M. McIntosh, Peter M. Visscher, Ian J. Deary, Simon R. Cox, Duncan Sproul
Journal: Genome biology (2022)

Abstract Background DNA methylation is an epigenetic mark associated with the repression of gene promoters. Its pattern in the genome is disrupted with age and these changes can be used to statistically predict age with epigenetic clocks. Altered rates of aging inferred from these clocks are observed in human disease. However, the molecular mechanisms underpinning age-associated DNA methylation changes remain unknown. Local DNA sequence can program steady-state DNA methylation levels, but how it influences age-associated methylation changes is unknown. Results We analyze longitudinal human DNA methylation trajectories at 345,895 CpGs from 600 individuals aged between 67 and 80 to understand the factors responsible for age-associated epigenetic changes at individual CpGs. We show that changes in methylation with age occur at 182,760 loci largely independently of variation in cell type proportions. These changes are especially apparent at 8322 low CpG density loci. Using SNP data from the same individuals, we demonstrate that methylation trajectories are affected by local sequence polymorphisms at 1487 low CpG density loci. More generally, we find that low CpG density regions are particularly prone to change and do so variably between individuals in people aged over 65. This differs from the behavior of these regions in younger individuals where they predominantly lose methylation. Conclusions Our results, which we reproduce in two independent groups of individuals, demonstrate that local DNA sequence influences age-associated DNA methylation changes in humans in vivo. We suggest that this occurs because interactions between CpGs reinforce maintenance of methylation patterns in CpG dense regions.
70P Genetic alterations and immune cell infiltration with potential impact on PD-(L)1 targeted treatment in various cancer entities: Biobank research project of the INFINITY registry
Authors: C. Vannier, P. Jermann, M. Matter, H. Läubli, S. Grebhardt, P. Wright, B. Kasenda, N.W. Marschner
Journal: Annals of Oncology (2022)
14P Up-regulated PI3K/mTOR/AKT pathway behind the downregulation of PTEN, FBXW7, genes and miRNA 140-145, ALK mediated chemotherapy resistance in non-small cell lung carcinoma (NSCLC)
Authors: M.J. Aslam, M.N. Faisal, H. Nazeer, J. Hussain, H. Muzaffar, A. Mahmood, H. Javed, Q. Tanveer
Journal: Annals of Oncology (2022)
56P The prognostic role of KRAS mutations in patients with early-stage lung adenocarcinoma after robotic lobectomy and systematic lymphadenectomy
Authors: F.T. Gallina, D. Marinelli, D. Forcella, R. Tajè, S. Ceddia, F. Fusco, E. Melis, S. Buglioni, P. Visca, F. Cappuzzo, F. Facciolo
Journal: Annals of Oncology (2022)
93P Migrating cancer stem cell elimination by disrupting tumor-stroma crosstalk using CXCR4 targeting human endogenous peptides in PDAC
Authors: K. Tiwary, M. Harms, B. Beitzinger, R. Schmid, S. Inaas, A. Lahusen, K. Walter, A. Kleger, T. Seufferlein, M. Lindén, J. Münch, P.C. Hermann
Journal: Annals of Oncology (2022)
67P High levels of circulating ceramides are associated with poor prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC)
Authors: C. Cattrini, M. Manfredi, P. Barboro, M. Ghirimoldi, A. Mennitto, V. Martini, A. Battioni, M. Le Van, F. Biello, F. Platini, B. Ruffilli, C. Branni, A. Tassone, S. Gobbato, A. Stella, F. Catalano, E. Zanardi, D.J. Pinato, F. Boccardo, A. Gennari
Journal: Annals of Oncology (2022)
27P Clinical relevance of NGS analysis in endometrial cancer (EC) management
Authors: E. Giudice, V. Ghizzoni, M.V. Carbone, V. Salutari, S. Cappuccio, C. Nero, L. Musacchio, C. Ricci, F. Ciccarone, F. Camarda, M.T. Perri, D. Giannarelli, F. Fanfani, G. Scambia, D. Lorusso
Journal: Annals of Oncology (2022)